PROJECTABSTRACT Inmesialtemporallobeepilepsy(TLE),aninitialprecipitatingeventtriggersaprogressiveprocessof celldeathandcircuitreorganizationthatrendersneuralnetworkshyperexcitableandsusceptibletoabnormal synchronizedactivitythatmanifestsasspontaneousrecurringseizures.TLEisoneofthemostcommonand difficulttotreatformsoffocalepilepsyandisassociatedwithhippocampalneurodegenerationthatsparesthe CA2region.Inchronicallyepilepticanimalsseizurespropagatethroughthehippocampusdespitewidespread celldeathinCA1andCA3,suggestingthatepilepticactivitymaybegeneratedinorconveyedthrough survivingCA2circuitry.Furthermore,accumulatingevidencesuggeststhatCA2mayhaveanimportantrole controllinghippocampalnetworkexcitabilityandsynchrony,buttheunderlyingmechanismsremainunknown. ConsideringtogethertheresilienceoftheCA2regionanditsrolecontrollingnetworkexcitability,Ihypothesize thatinTLEtheCA2regionactsasacriticalhubsupportingthegenerationandpropagationofepileptiform activityinthehippocampalnetwork.Inaninvitromodelofpharmacologically-inducedepileptiformactivity acutesilencingofCA2PNsreducedpopulationburstinginCA1.Preliminarydatafromthepilocarpinemouse modelofTLEsuggestsenhancedexcitatorysynapticinputtoCA2inepilepticmiceandincreasedintrinsic excitabilityofCA2PNs.Furthermore,preliminarydatafromacollaborativestudybetweenourlaboratoryand thatofHelenScharfmanattheNathanKlineInstitutesuggestthatchronicsilencingofCA2inpilocarpine- treatedmicemayreducethefrequencyofspontaneousseizures.ThecontributionoftheCA2subfieldto hippocampalcircuitryandphysiologyremainsincompletelyunderstoodandchangestoCA2circuitryinTLE havenotbeeninvestigated.InadditiontoreceivinginputfromdentategyrusgranulecellsandCA3PNs,CA2 PNsreceiveexceptionallystrongexcitatoryinputfromtheentorhinalcortex.Inturn,CA2axonsprojectforward toCA1,extendbackwardsthroughoutCA3,andformlocalrecurrentconnectionsthatexciteotherCA2PNs. CA2back-projectionsalsoenterthehilusoftheDG,butthiscircuithasnotbeencharacterized.Thus,CA2, CA3,andtheDGtogetherformahighlyinterconnectedrecurrentnetworkthatmaybecomeahyperexcitable hubunderpathologicalconditions.ItisessentialtodefinehowCA2circuitrychangesinchronicepilepsy,and inturn,howthesealteredcircuitscontributetopathophysiologicalactivity.Toaddressthesegapsin knowledge,IwilluseoptogeneticapproachesinvitroandinvivousingtheAmigo2-Cremouseline,which drivesexpressionselectivelyinCA2pyramidalneurons.UsingthepilocarpinemousemodelofTLE,Iwill characterizeCA2circuitryinnormalandepilepticmiceandidentifythechangestoCA2circuitrythat accompanyepileptogenesisanddetermineifmodulationofCA2activityinfluenceschronicseizures.These experimentswilladvanceourunderstandingoftheroleoftheCA2regionincontrollinghippocampalnetwork excitabilityandthegenerationofseizuresinamodelofmesialtemporallobeepilepsy.